Mattitolonen.fi2

REF. 9). Iproniazid, a drug registered for the
treatment of tuberculosis, was found to elevate the mood of patients that received it,and subsequent studies in patients who were
Is mood chemistry?
depressed but did not have tuberculosisshowed its effect as an antidepressant9. Sim-ultaneously and independently, imipramine,
Eero Castrén
an experimental antihistamine with a tricyclicstructure, was found to have antidepressant
Abstract The chemical hypothesis of
searching for the genes that might be asso-
effects. These discoveries revolutionized the
depression suggests that mood disorders
ciated with these familial disorders, and
recognition and treatment of mood disorders.
are caused by a chemical imbalance in the
researchers hope to uncover a molecule that is
In retrospect, it seems unbelievable that
brain, which can be corrected by
malfunctioning in people with depression8.
imipramine was introduced to the market
antidepressant drugs. However, recent
These research strategies seem to be based on
only several years after its antidepressant
evidence indicates that problems in
an extension of the monoamine hypothesis,
effects were discovered, mainly because the
information processing within neural
the chemical hypothesis of depression (FIG. 2),
company producing it was unsure that the
networks, rather than changes in chemical
which proposes that mood disorders are
number of patients who would benefit from
balance, might underlie depression, and that
caused by structural or functional changes in
antidepressant treatment was sufficiently
antidepressant drugs induce plastic changes
particular molecules in the brain, and that
high9. This now sounds incredible given the
in neuronal connectivity, which gradually lead
antidepressants function by counteracting
current estimate that major depression is
to improvements in neuronal information
these molecular changes. Over the last few
the single most expensive disorder faced
processing and recovery of mood.
decades, the view that depression is produced
by Western societies and that, overall, anti-
by a chemical imbalance in the brain has
depressants are among the best selling drugs.
The first antidepressants were discovered by
become widely accepted among scientists,
Soon after this discovery, imipramine and
chance almost 50 years ago, when drugs that
clinicians and the public.
iproniazid were found to increase the extra-
had been developed for other disorders were
However, during the past decade, several
cellular concentrations of two important
found to elevate the mood of psychiatric
observations indicated that there might be
neurotransmitters — serotonin and nor-
patients. Soon after this, drugs with anti-
an alternative hypothesis to the chemical
adrenaline — in the brain, by blocking their
depressant activity were shown to increase the
view of depression. This network hypothesis
re-uptake back to nerve endings or by
extracellular concentrations of two important
proposes that mood disorders reflect pro-
inhibiting the main metabolizing enzyme,
monoamine neurotransmitters in the brain —
blems in information processing within par-
monoamine oxidase, respectively. As drugs
serotonin (5-hydroxytryptamine or 5-HT) and
ticular neural networks in the brain and that
that alleviate depression increase extracellular
noradrenaline — by inhibiting their cata-
antidepressant drugs and other treatments
monoamine concentrations, it was proposed
bolism or reuptake to nerve endings. These
that alleviate depression function by gradu-
that depression might be produced by a
findings were the basis for the monoamine
ally improving information processing
serotonin or noradrenaline deficiency at
hypothesis of depression, which proposes that
within these networks (FIG. 3). This review
functionally important receptor sites in the
mood disorders are caused by a deficiency in
discusses the evidence supporting and con-
brain1–4 (FIG. 1), a proposal that is now known
serotonin or noradrenaline at functionally
tradicting the network hypothesis and the
as the monoamine hypothesis of depression.
important receptor sites in the brain1–4 (FIG.1).
implications of the network view on drug
Initially, the idea that a complex psychiatric
It soon became evident that the
development and the treatment of mood
disorder such as depression could be pro-
monoamine hypothesis in its original form
duced by biochemical changes was met with
could not explain all of the effects of anti-
widespread scepticism among psychiatrists
depressants5. Therefore, the focus of research
The chemical hypothesis
and laymen. Nevertheless, during the last few
was directed towards the receptors and intra-
We will soon be celebrating the fiftieth
decades this hypothesis has strongly influ-
cellular signal transduction molecules that are
anniversary of the discovery of antidepres-
enced views about the pathophysiology of
regulated by antidepressant treatment6,7.
sants, although the exact date and place of
mood disorders, among not only pharma-
Furthermore, because mood disorders often
the discovery is a matter of dispute (for the
cologists, but also clinicians, other scientists
run in families, genetic studies have been
history of the discovery of antidepressants, see
and the public4.
NATURE REVIEWS NEUROSCIENCE
VOLUME 6 MARCH 2005 2 4 1 2005 Nature Publishing Group
principal role of the nervous system is not tohandle chemicals but to store and processinformation. Arvid Carlsson, one of the mainarchitects of the concept of chemical neuro-transmission in the brain, stated in his Nobellecture, ‘However, it must be recognized thatthe brain is not a chemical factory but anextremely complicated survival machine'18.Although chemical neurotransmitters are
crucial for the transfer of information bet-
Figure 1 Monoamine hypothesis of mood disorders. a In the normal brain, monoamine
ween neurons, information in the brain is not
neurotransmitters (yellow) are released and bind to receptors on the postsynaptic neuron. Transmission is
stored in a chemical form but is thought to be
terminated by re-uptake of the transmitter. b In depression, the decreased concentration of monoamine at
processed by the complex interactions of neu-
synaptic sites produces a mood disorder. c Blockade of the re-uptake sites (grey) increases the
rons in neural networks19,20. These networks
concentration of monoamine neurotransmitters available at receptor sites and restores mood.
develop through interactions with the envi-ronment, and the neuronal structure of, andneurotransmission in these networks are con-
The monoamine hypothesis focused the
growth factors and their receptors, and
stantly being refined through activity-depen-
interest of the pharmaceutical industry on
intracellular signalling molecules4,6,7,15 (FIG. 2).
dent synaptic plasticity to optimally process
monoamine metabolism for decades.
As a result of this development, the mono-
and store relevant information21 (BOX 1). So,
Imipramine, which inhibits the re-uptake of
amine hypothesis has evolved to what could
disorders of the nervous system, including
both serotonin and noradrenaline (and vari-
be called a chemical or molecular hypothesis
depression, might represent disturbances in
ous other receptors and enzymes), has now
of depression. This hypothesis presumes that
the activity-dependent information process-
been largely replaced by a host of molecules
mood disorders are produced by long-term
ing of the brain, rather than in the chemical
that inhibit the uptake of either serotonin or
changes in the production or activity of mol-
balance of signalling molecules.
noradrenaline more selectively, and ipron-
ecules in the brain and that antidepressants
It should be noted that the chemical and
iazid, which inhibits monoamine oxidase,
function by counteracting these molecular
network hypotheses are not mutually exclu-
the main metabolizing enzyme for mono-
changes. Motivated by this hypothesis,
sive, but are complementary. As the synthesis
amines, has given way to subtype-selective
researchers are using large-scale DNA micro-
and release of several important signalling
monoamine oxidase inhibitors. Although
array searches to look for genes that are up- or
molecules are regulated by neuronal activity,
this focused drug development effort has
downregulated in depression or by anti-
changes in the activity of neural networks
clearly been successful from the point of view
depressant treatments, in the hope that the
produce changes in the concentration of these
of safety, it has been less successful in terms
molecules that are encoded by these genes
signalling molecules. Therefore, although
of efficacy. Modern antidepressants are no
might be used as targets in the development
the initial effects of antidepressants are obvi-
more effective than the first generation of
of new antidepressant drugs4,16,17.
ously chemical and are, in most cases, directed
drugs that were discovered several decades
towards the metabolism of monoamines, the
ago, and electroconvulsive shock treatment
ensuing adaptive changes in the concentra-
remains the most effective treatment for
tions of those signalling molecules are tightly
It was recognized early on
linked to the structure of the neural network,
It was recognized early on that several
that several observations
and might be a consequence of the altered
observations conflict with a simple link
information processing rather than its cause.
conflict with a simple link
between monoamine concentrations in the
According to this view, antidepressants initiate
brain and depression11. For example, deple-
between monoamine
a ‘self-repair' process, whereby plasticity in
tion of dietary tryptophan, which signifi-
neural networks and chemical neurotrans-
concentrations in the brain
cantly decreases the concentration of sero-
mission indivisibly cooperate and gradually
tonin in the brain, produces either no effects
and depression.
bring about mood elevation.
or only a mild dysphoria in healthy volunteersand does not influence the mood of untreated
Evidence for the network hypothesis
patients with depression12,13. More impor-
The network hypothesis
The evidence that supports the network
tantly, although the effects of antidepressants
But is this view correct? Is mood chemistry?
hypothesis of depression and antidepressant
on monoamine metabolism can be seen soon
Observations that have been made during the
action is limited and mostly indirect. Part of
after administration, it typically takes several
last few years indicate that there might be an
the problem is the lack of appropriate
weeks of continued treatment for the clinical
alternative to the chemical view of depression
experimental models of depression. In par-
antidepressant response to appear11. The dis-
and the action of antidepressants5. This new
ticular, there are no relevant and widely
covery that long-term antidepressant treat-
hypothesis, the network hypothesis, proposes
accepted in vitro models of what might be
ment produces adaptive changes in
that problems in activity-dependent neuronal
going on in the brain during depression.
monoamine receptors and in their coupling
communication might underlie depression,
Furthermore, methods for direct measure-
to intracellular signal transduction14 caused
and that antidepressants might work by
ment of changes in neural networks in vivo
the research focus to shift towards the effects
improving information processing in the
are only now being developed and have not
that long-term antidepressant treatments
affected neural networks (FIG. 3). A key aspect
yet been applied to neuropharmacological
have on the concentrations of neuropeptides,
of the network view is the recognition that the
2 4 2 MARCH 2005 VOLUME 6 2005 Nature Publishing Group
Imaging studies in patients with depres-
sion have revealed reduced grey matter
volume in the prefrontal cortex32–34 and the
hippocampus35–39. Morphological changes in
the hippocampus are associated with, andmight be preceded by, functional deficits,
such as memory impairment35. As the neu-
ronal processes and synapses take up most of
the space in the grey matter, reduced volumemight mean reduced neuronal complexity
and connectivity. To at least some degree,
these morphological alterations seem to be
reversible by antidepressant therapies34,40.
The results of a recent study show that
reduced hippocampal volume is particularly
common in patients with depression who
suffered a childhood trauma41, which indi-
Cytocrome c
cates that severe stress during a critical devel-
opmental period might have lasting effects
on the morphology of the brain. These data
support the hypothesis that mood disordersare associated with compromised informa-
tion processing in crucial neural networks,
Failure of
and that the action of antidepressants might
result in morphological and physiologicalreorganization of specific neuronal connec-tions in the brain. Furthermore, imaging andgenetic studies are beginning to elucidate
Genetic and
which neural structures are involved in differ-ent mental health disorders and which circuits
Figure 2 The chemical hypothesis of depression. The intracellular pathways that are affected by
might be important targets for successful
mood disorders and antidepressants. AKT, protein kinase B; BAD, BLC-associated death promoter;BCL2, B-cell leukaemia/lymphoma 2; BCL-X, BCL2-like protein 1; BDNF, brain-derived neurotrophic
factor; CREB, cyclic AMP responsive element binding protein; ERK, mitogen activated protein
Perhaps the most important evidence for
kinase 1; GR, glucocorticoid receptor; GSK3, glycogen synthase kinase 3; MEK, ERK kinase;
the network hypothesis is the recent obser-
VPA, valproate; NA, noradrenaline; P, phosphate; RAF, RAF proto-oncogene; ROS, reactive oxygen
vation that antidepressants increase the
species; Ras GTP, Ras GTPase-activating protein; RSK2, ribosomal protien S6 kinase polypeptide 3;
production of new neurons in the rodent
TRKB, neurotrophic tyrosine kinase receptor type B; 5-HT, 5-hydroxytryptamine (serotonin).
hippocampus42. Importantly, the increased
Adapted, with permission, from REF. 6 (2001) Macmillan Magazines Ltd.
neurogenesis that is brought about bychronic antidepressant treatment correlateswith the behavioural effects produced by
Monoamines, particularly serotonin,
It is well known that the plasticity of neural
antidepressants43. Newly generated neurons
have a significant role during brain develop-
connectivity in the brain is greater and more
differentiate over time, and are only mature
ment23. Genetic elimination of the 5-HT1A
extensive during critical periods of postnatal
enough to participate in information
receptor produces anxiety-type behaviour in
development than in adults, and that func-
processing several weeks after their birth44.
adult mice, but only when the receptor was
tional structures that are formed during
The fact that this time course correlates with
absent during early postnatal development
critical periods remain relatively stable in
the delayed onset of the clinical effects of
— its absence in adulthood produces no
adulthood31 (BOX 1). These data highlight the
antidepressants has created a lot of excite-
behavioural effects24. Furthermore, muta-
effects that serotonin and antidepressant
ment among neuropharmacologists. In the
tions in monoamine oxidase A produce
treatments have on the plasticity of neural
hippocampi of rodents that have received
behavioural alterations in both men and
networks, and link the effects of antidepres-
antidepressant treatment, the elimination of
mice25,26, and disrupt the developmental
sants with the environmental manipulations
neurons through apoptotic cell death
organization of thalamocortical inputs and
that are known to modulate neural network
increases simultaneously with increased
cortical modules in the brains of rodents23,27.
formation during development31. Moreover,
neurogenesis, which indicates that antide-
A similar disruption in thalamocortical
they indicate that the effects of the drugs
pressants might increase neuronal turnover
organization has also been produced with
might be more robust in the brain during
rather than neurogenesis per se45. This effect
the administration of antidepressants and
early postnatal development and qualita-
might be functionally analogous to the
monoamine oxidase inhibitors during early
tively different when compared with the
overproduction of neurons that occurs
postnatal development27,28. Furthermore,
effects seen in the adult brain, which could
during the development of the peripheral
antidepressant treatment during early post-
have significant implications for the pre-
nervous system (BOX 1), and indicates that
natal life can produce permanent behav-
scription of antidepressants to children and
antidepressants might facilitate optimiza-
ioural disturbances in adult animals29,30.
pregnant mothers.
tion of neuronal connectivity by increasing
NATURE REVIEWS NEUROSCIENCE
VOLUME 6 MARCH 2005 2 4 3 2005 Nature Publishing Groupa Healthyb Depressed
of BDNF in the hippocampus and cortex52–54,and the injection of BDNF into the brain oroverexpression of its receptor in transgenicmice produces similar behavioural responsesto those typically observed after treatmentwith antidepressant drugs55,56. Consistentwith the importance of BDNF in the effectsof antidepressants, transgenic mice withreduced BDNF expression or signalling fail to show these characteristic behaviouralresponses after the administration of anti-depressants54, which indicates that normalBDNF signalling might be both necessary andsufficient for a normal antidepressant effect. Itshould be emphasized that the crucial point isnot the increased molecular concentrationsof BDNF as such, but the importance ofthis neurotrophin as a mediator of activity-dependent neuronal plasticity (BOX 1).
In conclusion, the data that are summa-
rized above provide some evidence that anti-
c During treatmentd Recovered
depressants, through their acute effects onmonoamine metabolism, activate processesof plasticity, which are thought to graduallylead to improved information processing inthe neural networks that are involved inmood regulation. These processes, whichinclude neurogenesis and selective neuralelimination, arborization and retraction ofaxons and dendrites, and synaptic formationand pruning, are expected to take time todevelop and mature, which is consistent withthe delayed appearance of the clinical effectsof antidepressants.
However, observations have also been
made that seem to be incompatible with thenetwork hypothesis. Although depletion of tryptophan — the rate-limiting factor ofserotonin synthesis — does not influence themood of healthy volunteers and untreatedpatients with depression12,13,57, it does pro-
Figure 3 The network hypothesis of depression. a In the healthy brain, information is processed
duce a rapid relapse of depressive symptoms
in partially overlapping neural networks. b In depression, information processing in some networks
in about 50% of remitted patients who are
does not function properly. c Antidepressant treatment enhances connectivity in neural networks. d Activity-dependent pruning of synapses selects out and stabilizes the active synapses and networks.
being, or have recently been treated withserotonin selective antidepressants12,13.Furthermore, there is a circadian variation
the choice of neurons available for selection
connectivity without any net change in
in mood, and sleep deprivation rapidly
through activity-dependent mechanisms. At
synaptic number20. Unfortunately, it is difficult
improves the mood of patients with depres-
a more subtle level, antidepressant drugs
to quantify synaptic turnover in vivo.
sion, albeit temporarily58. These relatively
can enhance the sprouting of axons46 and
One possible mechanism through which
rapid effects on mood are difficult to recon-
dendrites47, and support the morphological
antidepressants might enhance the plasticity
cile with the view of their production by a
maturation of the newborn neurons47.
of neuronal connections in the hippocampus
gradual change in the structure of mood-
These data indicate that, in addition to their
and cerebral cortex is the activation of neuro-
elevating neural networks. It is obvious that
established function in elevating neuronal
trophin signalling48,49. Brain-derived neuro-
more experimental work will be necessary to
turnover in the dentate gyrus, antidepres-
trophic factor (BDNF), which is produced
test the new model, but the rapid develop-
sants might also stimulate the turnover of
and released by neurons in an activity-
ment of neurophysiological methods and
axonal branches and synaptic contacts,
dependent manner50, has been proposed to
the imaging of neural networks will help us
thereby providing more material for activ-
be a crucial factor in the selection and stabi-
to gain further insights into the relationship
ity-dependent selection. It should be noted
lization of active synaptic contacts51 (BOX 1).
between the effects of antidepressants and
that increased synaptic turnover might lead
Both antidepressants and electroconvulsive
neural plasticity, which might become a
to significant reorganization of neuronal
shocks increase the expression and signalling
fruitful area of further research.2 4 4 MARCH 2005 VOLUME 6 2005 Nature Publishing Group
be expected to be more beneficial than either
Box 1 Activity-dependent refinement of neural networks
treatment alone, and there is evidence that
During the development of the peripheral nervous system, neurons are produced in excess
this might be the case59. As the network
and compete to innervate the target tissues61. Neurotrophic factors, which are secreted by
hypothesis emphasizes the importance of
the target tissues (for example, muscles) in limited quantities, and which are required by
environmental information in the process of
innervating neurons for their survival, select from the competing neurons those that best
activity-dependent selection of neurons and
innervate the target, and the defeated neurons are eliminated by apoptosis. This competitive
synapses (BOX 1), it predicts that full recovery
process matches the number of neurons and targets and ensures optimal innervation of the
would not even be possible with drug treat-
target cells61–63. In the CNS, neurons target other neurons and competitive selection takes
ment alone, but that external stimuli, such as
place at several levels: among neurons (as in the peripheral nervous system), among axon
social communication, would be required to
branches and among synaptic contacts64. In the brain, the release of target-derived trophic
provide environmental input for the selec-
factors is activity dependent: the innervating neuron must sufficiently stimulate the target
tion of the appropriate network connections
neuron in order to induce the production and release of the trophic factor50,51. Neurons can
(FIG. 3). The role of environmental stimula-
also cooperate to increase the release of trophic factors: simultaneously active neurons that
tion might also be related to the fact that
innervate the same target neuron can induce the release of trophic factors through a much
major depression is typically cyclical and
lower level of activity than is required for a single innervating neuron51. This activity-
often self-limiting, and many patients
dependent cooperative selection of simultaneously active neurons and the elimination of
improve with time even in the absence of
inactive and incoherent contacts is considered to be crucial in the development of large,coherently active neural networks: ‘the neurons that fire together, wire together'21. Through
active treatment.these mechanisms, neuronal structure and neurotransmission are optimized to best store
Finally, the effects of antidepressant drugs
and process relevant information. During critical periods in early postnatal development,
on network plasticity in the brain might
much larger changes in the connectivity and organization of neural networks take place
explain why they are effective for many
than is possible in the adult brain31. Nevertheless, even the adult brain still shows significant
neuropsychiatric disorders, including anxiety,
plasticity. The crucial event in activity-dependent plasticity is not the formation of neuronal
obsessive-compulsive disorder, eating dis-
contacts (which might occur stochastically and in excess) but the activity-dependent
orders, chronic pain and tinnitus. It has been
selection and stabilization of those synapses that mediate useful signals, together with the
proposed that some of these disorders, par-
selective pruning and elimination of those that produce random noise20. Therefore,
ticularly chronic pain, might be produced by
neurogenesis and synaptogenesis cannot simply be considered beneficial, and neuronal
aberrant neuronal connectivity60.death and synapse elimination harmful; what matters is the optimization of the
The hypothesis that mood represents a
signal–to–noise ratio in the network. Neurotrophins are important in this process through
functional state of neural networks might
their selective release from active connections; indiscriminate increases in the levels of
sound incompatible with the efforts of ratio-
neurotrophic factors or their signalling (as, for example, would be produced by a
nal drug development. However, the data
neurotrophic factor receptor agonist) is not expected to be beneficial to the network, as both
reviewed above indicate that the antidepres-
active and inactive connections would be similarly supported.
sant drugs that have been used successfullyfor several decades might function by initi-ating such plastic processes, apparently
plasticity. Therefore, psychological and
indirectly, by influencing monoamine
The view of mood disorders as problems of
pharmacological therapies, electroconvulsive
metabolism. It is possible that a similar
information processing in the brain has
shock treatment and placebo effects might all
process could also be initiated through
several important implications. As devel-
lead to improved information processing and
other pharmacological mechanisms, which
opmental neurobiologists have been investi-
mood recovery through mechanisms that ini-
might become the targets of new anti-
gating activity-dependent plastic processes
tiate similar processes of plasticity (FIG. 4). In
depressants that could help patients who are
for decades, collaboration between neuro-
this scenario, a combination of drug treat-
resistant to current drugs and only respond
pharmacologists, developmental neuro-
ment and psychological rehabilitation would
to electroconvulsive shock treatment.
scientists and behavioural geneticists shouldbe encouraged. Recent studies clearly showthat genetic manipulation of neural circuitsand assessment of the consequences through
in vivo recording techniques and behav-ioural assays might provide an incrediblepotential for begining to define the relation-ship between circuit properties, behaviouraldeficits and potential therapeutics23,24.
During development and in adults, train-
ing and rehabilitation produce functional andanatomical changes in neural networks,which are reflected in the gradual improve-
ment of the rehearsed action. Analogously,
psychotherapy, cognitive behavioural therapy
Figure 4 A combinatorial approach for treating depression based on the network hypothesis.
and other forms of psychological rehabilitation
Depression might reflect disturbed information processing in neural networks (left panel). Antidepressant
could also have therapeutic effects on mood
drugs, electroconvulsive shock and psychotherapy can all induce activity-dependent plasticity, which
disorders through use-dependent neuronal
gradually leads to the recovery of connectivity in the affected neural networks (right panel).
NATURE REVIEWS NEUROSCIENCE
VOLUME 6 MARCH 2005 2 4 5 2005 Nature Publishing Group
18. Carlsson, A. A half-century of neurotransmitter research:
45. Sairanen, M., Lucas, G., Ernfors, P., Castrén, M. &
Our view of mood disorders and the
impact on neurology and psychiatry. Nobel lecture.
Castrén, E. BDNF and antidepressant drugs have
action of antidepressants is beginning to
different but coordinated effects on neuronal turnover,
proliferation and survival in the adult dentate gyrus.
change from a chemical view towards a net-
19. Buzsaki, G. Large-scale recording of neuronal
J. Neurosci. 25, 1089–1094 (2005).
work hypothesis, in which problems in infor-
ensembles. Nature Neurosci. 7, 446–451 (2004).
46. Vaidya, V. A., Siuciak, J. A., Du, F. & Duman, R. S.
20. Hua, J. Y. & Smith, S. J. Neural activity and the dynamics
Hippocampal mossy fiber sprouting induced by chronic
mation processing and neuronal connectivity
of central nervous system development. Nature
electroconvulsive seizures. Neuroscience 89, 157–166
in the brain are the central questions.Neurosci. 7, 327–332 (2004).
21. Katz, L. C. & Shatz, C. J. Synaptic activity and the
47. Fujioka, T., Fujioka, A. & Duman, R. S. Activation of cAMP
However, several important issues have yet to
construction of cortical circuits. Science 274, 1133–1138
signaling facilitates the morphological maturation of
be addressed. How are neural networks
newborn neurons in adult hippocampus. J. Neurosci. 24,
22. Varela, F., Lachaux, J. P., Rodriguez, E. & Martinerie, J.
319–328 (2004).
formed and sustained during development
The brainweb: phase synchronization and large-scale
48. Altar, C. A. Neurotrophins and depression. Trends
and in adults? Which neuronal connections
integration. Nature Rev. Neurosci. 2, 229–239 (2001).Pharmacol. Sci. 20, 59–61 (1999).
23. Gaspar, P., Cases, O. & Maroteaux, L. The
49. Castrén, E. Neurotrophic effects of antidepressant drugs.
are involved, and are the same networks
developmental role of serotonin: news from mouse
Curr. Opin. Pharmacol. 4, 58–64 (2004).
affected in all patients? How do antidepres-
molecular genetics. Nature Rev. Neurosci. 4, 1002–1012
50. Thoenen, H. Neurotrophins and neuronal plasticity.Science 270, 593–598 (1995).
sants initiate and support the process of plas-
et al. Serotonin
receptor acts during
51. Poo, M. M. Neurotrophins as synaptic modulators.
ticity? Does the delayed appearance of clini-
development to establish normal anxiety-like behaviour in
Nature Rev. Neurosci. 2, 24–32 (2001).
the adult. Nature 416, 396–400 (2002).
52. Nibuya, M., Morinobu, S. & Duman, R. S. Regulation of
cal antidepressant effects reflect slow
25. Brunner, H. G., Nelen, M., Breakefield, X. O., Ropers, H. H.
BDNF and trkB mRNA in rat brain by chronic
maturation of neuronal connections, and
& van Oost, B. A. Abnormal behavior associated with a
electroconvulsive seizure and antidepressant drug
point mutation in the structural gene for monoamine
treatments. J. Neurosci. 15, 7539–7547 (1995).
could these processes be accelerated? In any
oxidase A. Science 262, 578–580 (1993).
53. Russo-Neustadt, A. A., Beard, R. C., Huang, Y. M. &
case, it is increasingly evident that the activ-
et al. Aggressive behavior and altered amounts
Cotman, C. W. Physical activity and antidepressant
of brain serotonin and norepinephrine in mice lacking
treatment potentiate the expression of specific brain-
ity-dependent plasticity and connectivity of
MAOA. Science 268, 1763–1766 (1995).
derived neurotrophic factor transcripts in the rat
neural networks must be considered when
et al. Lack of barrels in the somatosensory
hippocampus. Neuroscience 101, 305–312
cortex of monoamine oxidase A-deficient mice: role of a
designing future strategies of antidepressant
serotonin excess during the critical period. Neuron 16,
54. Saarelainen,
et al. Activation of the TrkB neurotrophin
treatment, whether they are pharmacologi-
297–307 (1996).
receptor is induced by antidepressant drugs and is
28. Xu, Y., Sari, Y. & Zhou, F. C. Selective serotonin reuptake
required for antidepressant-induced behavioral effects.
cal, psychological or combinatorial.
inhibitor disrupts organization of thalamocortical
J. Neurosci. 23, 349–357 (2003).
somatosensory barrels during development. Dev. Brain
55. Shirayama, Y., Chen, A. C., Nakagawa, S., Russell, D. S.Eero Castrén is at the Neuroscience Center,Res. 150, 151–161 (2004).
& Duman, R. S. Brain-derived neurotrophic factor
University of Helsinki, Finland.
29. Ansorge, M. S., Zhou, M., Lira, A., Hen, R. & Gingrich, J. A.
produces antidepressant effects in behavioral
Early-life blockade of the 5-HT transporter alters
models of depression. J. Neurosci. 22, 3251–3261
emotional behavior in adult mice. Science 306, 879–881
56. Siuciak, J. A., Lewis, D. R., Wiegand, S. J. & Lindsay, R. M.
30. Feng, P., Ma, Y. & Vogel, G. W. The critical window of
Antidepressant-like effect of brain-derived neurotrophic
Bunney, W. E. Jr & Davis, J. M. Norepinephrine in
brain development from susceptive to insusceptive.
factor (BDNF). Pharmacol. Biochem. Behav. 56, 131–137
depressive reactions. A review. Arch. Gen. Psychiatry 13,
Effects of clomipramine neonatal treatment on sexual
483–494 (1965).
behavior. Brain Res. Dev. Brain Res. 129, 107–110
57. Van der Does, A. J. W. The effects of tryptophan
Coppen, A. The biochemistry of affective disorders. Br.
depletion on mood and psychiatric symptoms. J. Affect.J. Psychiatry 113, 1237–1264 (1967).
31. Berardi, N., Pizzorusso, T. & Maffei, L. Critical periods
Disord. 64, 107–119 (2001).
Schildkraut, J. J. The catecholamine hypothesis of
during sensory development. Curr. Opin. Neurobiol. 10,
58. Wirz-Justice, A. & Van den Hoofdakker, R. H. Sleep
affective disorders: a review of supporting evidence. Am.
138–145 (2000).
deprivation in depression: what do we know, where do
J. Psychiatry 122, 509–522 (1965).
32. Bremner, J. D. et al. Reduced volume of orbitofrontal
we go? Biol. Psychiatry 46, 445–453 (1999).
Wong, M. L. & Licinio, J. From monoamines to genomic
cortex in major depression. Biol. Psychiatry 51, 273–279
Adolescents With Depression Study
targets: a paradigm shift for drug discovery in
Team. Fluoxetine, cognitive-behavioral therapy, and
depression. Nature Rev. Drug Disc. 3, 136–150 (2004).
33. Botteron, K. N., Raichle, M. E., Drevets, W. C., Heath, A. C.
their combination for adolescents with depression:
Nestler, E. J. et al. Neurobiology of depression. Neuron
& Todd, R. D. Volumetric reduction in left subgenual
Treatment for Adolescents With Depression Study
34, 13–25 (2002).
prefrontal cortex in early onset depression. Biol.
(TADS) randomized controlled trial. JAMA 292, 807–820
Manji, H. K., Drevets, W. C. & Charney, D. S. The cellular
Psychiatry 51, 342–344 (2002).
neurobiology of depression. Nature Med. 7, 541–547
34. Drevets, W. C. Neuroimaging and neuropathological
60. Wolpaw, J. R. & Tennissen, A. M. Activity-dependent
studies of depression: implications for the
spinal cord plasticity in health and disease. Annu. Rev.
Coyle, J. T. & Duman, R. S. Finding the intracellular
cognitive–emotional features of mood disorders. Curr.Neurosci. 24, 807–843 (2001).
signaling pathways affected by mood disorder
Opin. Neurobiol. 11, 240–249 (2001).
61. Levi-Montalcini, R. The nerve growth factor: thirty-five
treatments. Neuron 38, 157–160 (2003).
35. MacQueen, G. M. et al. Course of illness, hippocampal
years later. EMBO J. 6, 1145–1154 (1987).
Kennedy, J. L., Farrer, L. A., Andreasen, N. C., Mayeux, R.
function, and hippocampal volume in major depression.
62. Barde, Y.-A. Trophic factors and neuronal survival.
& George-Hyslop, P. The genetics of adult-onset
Proc. Natl Acad. Sci. USA 100, 1387–1392 (2003).Neuron 2, 1525–1534 (1989).
neuropsychiatric disease: complexities and conundra?
36. Sheline, Y. I., Gado, M. H. & Kraemer, H. C. Untreated
63. Huang, E. J. & Reichardt, L. F. Neurotrophins: roles in
Science 302, 822–826 (2003).
depression and hippocampal volume loss. Am.
neuronal development and function. Annu. Rev.The Antidepressant Era (Harvard Univ. Press,
J. Psychiatry 160, 1516–1518 (2003).Neurosci. 24, 677–736 (2001).
Cambridge, Massachusetts, 1997).
37. Sheline, Y. I. Neuroimaging studies of mood disorder
64. Cohen-Cory, S. The developing synapse: construction
10. Duman, R. S. & Vaidya, V. A. Molecular and cellular
effects on the brain. Biol. Psychiatry 54, 338–352 (2003).
and modulation of synaptic structures and circuits.
actions of chronic electroconvulsive seizures. J. ECT 14,et al. Hippocampal changes in patients with a
Science 298, 770–776 (2002).
181–193 (1998).
first episode of major depression. Am. J. Psychiatry 159,
11. Nestler, E. J. Antidepressant treatments in the 21st
1112–1118 (2002).
century. Biol. Psychiatry 44, 526–533 (1998).et al. Quantitative MRI of the hippocampus
I would like to thank H. Rauvala, M. Saarma, M. Castrén and
12. Delgado, P. L. How antidepressants help depression:
and amygdala in severe depression. Psychol. Med. 30,
R. Galuske for their comments to the manuscript, and the Sigrid
mechanisms of action and clinical response. J. Clin.
117–125 (2000).
Jusélius Foundation, Sohlberg Foundation and the Academy of
Psychiatry 65 Suppl. 4, 25–30 (2004).
40. Drevets, W. C., Bogers, W. & Raichle, M. E. Functional
Finland and for support.
13. Booij, L., Van der Does, A. J. & Riedel, W. J. Monoamine
anatomical correlates of antidepressant drug treatment
depletion in psychiatric and healthy populations: review.
assessed using PET measures of regional glucose
Competing interests statement
Mol. Psychiatry 8, 951–973 (2003).
metabolism. Eur. Neuropsychopharmacol. 12, 527–544
The author declares no competing financial interests.
14. Sulser, F., Vetulani, J. & Mobley, P. L. Mode of action of
antidepressant drugs. Biochem. Pharmacol. 27,
41. Vythilingam,
et al. Childhood trauma associated with
257–261 (1978).
smaller hippocampal volume in women with major
Online links
15. Duman, R. S., Heninger, G. R. & Nestler, E. J.
depression. Am. J. Psychiatry 159, 2072–2080 (2002).
A molecular and cellular theory of depression. Arch. Gen.
42. Malberg, J. E., Eisch, A. J., Nestler, E. J. & Duman, R. S.Psychiatry 54, 597–606 (1997).
Chronic antidepressant treatment increases
The following terms in this article are linked online to:
16. Knuuttila, J. E., Toronen, P. & Castrén, E. Effects of
neurogenesis in adult rat hippocampus. J. Neurosci. 20,Mouse Genome Informatics: http://www.informatics.jax.org/
antidepressant drug imipramine on gene expression in rat
9104–9110 (2000).
prefrontal cortex. Neurochem. Res. 29, 1235–1244 et al. Requirement of hippocampal
neurogenesis for the behavioral effects of
17. Newton, S. S. et al. Gene profile of electroconvulsive
antidepressants. Science 301, 805–809 (2003).
seizures: induction of neurotrophic and angiogenic
44. van Praag, H. et al. Functional neurogenesis in the adult
factors. J. Neurosci. 23, 10841–10851 (2003).
hippocampus. Nature 415, 1030–1034 (2002).Access to this interactive links box is free online.2 4 6 MARCH 2005 VOLUME 6 2005 Nature Publishing Group

and Treatment of in Primary Care This educational activity is supported through pooled-funded educational grants from Pfizer Inc. and Abbott Laboratories to the Physicians' Institute for Excellence in Medicine to develop and offer grants to accredited CME providers for improvement in the diagnosis